RESUMEN
In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Viremia/tratamiento farmacológico , Adulto , Fármacos Anti-VIH , Infecciones por VIH/virología , Humanos , Estudios Prospectivos , Replicación ViralRESUMEN
In chronic viral infections of humans and experimental animals, virus-specific CD4(+) T cell function is believed to be critical for induction and maintenance of host immunity that mediates effective restriction of viral replication. Because in vitro proliferation of HIV-specific memory CD4(+) T cells is only rarely demonstrable in HIV-infected individuals, it is presumed that HIV-specific CD4(+) T cells are killed upon encountering the virus, and maintenance of CD4(+) T cell responses in some patients causes the restriction of virus replication. In this study, proliferative responses were absent in patients with poorly restricted virus replication although HIV-specific CD4(+) T cells capable of producing IFN-gamma were detected. In a separate cohort, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4(+) T cells were present. HIV-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4(+) T cells of viremic patients could be induced to proliferate in response to HIV antigens when costimulation was provided by anti-CD28 antibody in vitro. Thus, HIV-1-specific CD4(+) T cells persist but remain poorly responsive (produce IFN-gamma but do not proliferate) in viremic patients. Unrestricted virus replication causes diminished proliferation of virus-specific CD4(+) T cells. Suppression of proliferation of HIV-specific CD4(+) T cells in the context of high levels of antigen may be a mechanism by which HIV or other persistently replicating viruses limit the precursor frequency of virus-specific CD4(+) T cells and disrupt the development of effective virus-specific immune responses.
Asunto(s)
Linfocitos T CD4-Positivos/citología , Antígenos VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/crecimiento & desarrollo , Viremia/inmunología , Replicación Viral/inmunología , Linfocitos T CD4-Positivos/inmunología , División Celular , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Viremia/virologíaRESUMEN
A number of perturbations of B cells has been described in the setting of HIV infection; however, most remain poorly understood. To directly address the effect of HIV replication on B cell function, we investigated the capacity of B cells isolated from HIV-infected patients to respond to a variety of stimuli before and after reduction of viremia by effective antiretroviral therapy. B cells taken from patients with high levels of plasma viremia were defective in their proliferative responses to various stimuli. Viremia was also associated with the appearance of a subpopulation of B cells that expressed reduced levels of CD21. After fractionation into CD21(high)- and CD21(low)-expressing B cells, the CD21(low) fraction showed dramatically reduced proliferation in response to B cell stimuli and enhanced secretion of immunoglobulins when compared with the CD21(high) fraction. Electron microscopic analysis of each fraction revealed cells with plasmacytoid features in the CD21(low) B cell population but not in the CD21(high) fraction. These results indicate that HIV viremia induces the appearance of a subset of B cells whose function is impaired and which may be responsible for the hypergammaglobulinemia associated with HIV disease.
Asunto(s)
Linfocitos B/inmunología , Infecciones por VIH/inmunología , VIH-1/patogenicidad , Antígenos CD19/genética , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/ultraestructura , Linfocitos B/ultraestructura , Secuencia de Bases , Cartilla de ADN/genética , Expresión Génica , Infecciones por VIH/genética , Humanos , Hipergammaglobulinemia/etiología , Inmunofenotipificación , Activación de Linfocitos , Microscopía Electrónica , Receptores de Complemento 3d/genética , Receptores de Complemento 3d/metabolismo , Viremia/genética , Viremia/inmunologíaAsunto(s)
Alopecia/inducido químicamente , Fármacos Anti-VIH/efectos adversos , Enfermedad de Graves/inducido químicamente , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
CD8+ T cell-mediated antiviral activity against HIV has been described consistently in infected individuals; however, the role of this activity in controlling replication of HIV in the latently infected, resting CD4+ T cell reservoir is unclear. By using an ex vivo system, we show that replication of HIV in this viral reservoir is effectively suppressed in coculture by autologous CD8+ T cells in long-term nonprogressors (LTNPs) and in patients whose viremia was controlled by highly active antiretroviral therapy (HAART), but not in therapy-naive patients who had substantial levels of plasma viremia. This antiviral activity was largely independent of cytotoxic CD8+ T lymphocytes (CTL). When the role of soluble CD8+ T cell-derived factors was examined, we found that CC-chemokines played a major role in inhibition of viral replication in the latent viral reservoir in some LTNPs and patients receiving HAART, but not in chronically infected patients who were not receiving antiretroviral therapy. Potent antiviral activity, independent of CC-chemokines, was found mainly in patients in whom HAART was initiated shortly after the acute phase of HIV infection. These results indicate that CD8(+) T cells provide potent suppressive activity against HIV replication in the latent viral reservoir via direct cellular contact in patients who are naturally LTNPs or in those who are treated with HAART. Furthermore, the profound antiviral activity exerted by non-CC-chemokine soluble factors in infected patients who began HAART early in HIV infection suggests that preservation of this HIV-suppressive mechanism by early initiation of therapy may play an important role in the containment of viral replication in infected patients following interruption of therapy.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , VIH-1/fisiología , Replicación Viral , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Linfocitos T CD8-positivos/virología , Células Cultivadas , Quimiocina CCL4 , Quimiocina CCL5/análisis , Enfermedad Crónica , Técnicas de Cocultivo , Progresión de la Enfermedad , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Proteínas Inflamatorias de Macrófagos/análisis , Fenotipo , Latencia del VirusRESUMEN
Although skewing of the CD4+ TCR repertoire in advanced HIV infection is well documented, increases in polyclonality during antiretroviral therapy have been less consistently observed. Ten patients, each with documented abnormalities within the CD4+ TCR repertoire, were studied by CDR3 spectratyping, semiquantitative PCR, and SSCP during 9-26 months of therapy. Naive and memory cell phenotypes were analyzed by flow cytometry. Six of 10 patients showed increased polyclonality of their TCR repertoires, 1 showed no change, and 3 showed increased TCR skewing, despite suppressed viral replication. Overall, there was no significant change in the percentage of abnormal BV subfamilies (from a mean of 25.5 to 17.1%) or the percentage of naive CD4+ T cells (from a mean of 18 to 25%). Further, progression of TCR repertoire disruptions was observed in some patients even with suppression of plasma viral RNA below 500 copies/ml. Although a spectrum of changes may be seen within the CD4+ TCR repertoire in the setting of antiretroviral therapy, increases in polyclonality are observed in some patients.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Memoria Inmunológica , Receptores de Antígenos de Linfocitos T/genética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/metabolismo , Regiones Determinantes de Complementariedad/metabolismo , Quimioterapia Combinada , Citometría de Flujo , Variación Genética/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T/metabolismo , Transcripción Genética , Replicación ViralRESUMEN
CD4(+) T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8(+) CTL response in murine models. Recent studies have demonstrated that CD4(+) T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells. The role of CD4(+) T cell help in the expansion of virus-specific CD8(+) memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4(+) T cell help was required for optimal in vitro expansion of influenza-specific CTL responses. Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4(+) T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4(+) T cell help was required for optimal expansion of HIV-1-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4(+) T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4(+) T cell help. In those HIV-1-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8(+) memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2. Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4(+) T cell-depleted conditions, where IL-2 is lacking.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/fisiología , Epítopos de Linfocito T/inmunología , VIH-1/inmunología , Memoria Inmunológica , Activación de Linfocitos/inmunología , Cooperación Linfocítica , Linfocitos T Citotóxicos/inmunología , Adyuvantes Inmunológicos/fisiología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Comunicación Celular/inmunología , Separación Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/fisiología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Infecciones por VIH/inmunología , Humanos , Virus de la Influenza A/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/virologíaRESUMEN
The impact of HIV-associated immunopathogenesis on B cells has been largely associated with indirect consequences of viral replication. This study demonstrates that HIV interacts directly with B cells in both lymphoid tissues and peripheral blood. B cells isolated from lymph node and peripheral blood mononuclear cells (PBMCs) of 4 and 23 chronically infected patients, respectively, demonstrated similar capacities to pass virus to activated HIV-negative PBMCs when compared with CD4(+) cells from the same patients. However, in contrast to T cells, virus associated with B cells was surface bound, as shown by its sensitivity to pronase and the staining pattern revealed by in situ amplification of HIV-1 RNA. Cell sorting and ligand displacing approaches established that CD21 was the HIV-binding receptor on B cells, and that this association was mediated through complement-opsonized virus. These B cells were also found to express significantly lower levels of CD21 compared with HIV-negative individuals, suggesting a direct perturbing effect of HIV on B cells. These findings suggest that B cells, although they themselves are not readily infected by HIV, are similar to follicular dendritic cells in their capacity to serve as extracellular reservoirs for HIV-1. Furthermore, B cells possess the added capability of circulating in peripheral blood and migrating through tissues where they can potentially interact with and pass virus to T cells.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Linfocitos B/virología , Complemento C3/fisiología , VIH-1/fisiología , Activación de Linfocitos , Receptores de Complemento 3d/fisiología , Linfocitos T/virología , Virión/fisiología , Síndrome de Inmunodeficiencia Adquirida/virología , Anticuerpos Monoclonales/inmunología , Enfermedad Crónica , Humanos , ARN Viral/análisisRESUMEN
It has been suggested that CD4+ T cell proliferative responses to HIV p24 Ag may be important in the control of HIV infection. However, these responses are minimal or absent in many HIV-infected individuals. Furthermore, while in vitro and in vivo responses to non-HIV recall Ags improve upon administration of highly active antiretroviral therapy, there does not appear to be a commensurate enhancement of HIV-specific immune responses. It is possible that CD4+ p24-specific T cells are deleted early in the course of infection. However, it is also possible that a discrete unresponsiveness, or anergy, contributes to the lack of proliferation to p24. To evaluate the possible contribution of unresponsiveness to the lack of CD4+ T cell proliferation to p24 in HIV-infected individuals, we attempted to overcome unresponsiveness. CD40 ligand trimer (CD40LT) and IL-12 significantly increased PBMC and CD4+ T cell proliferative responses to p24 Ag in HIV-infected, but not uninfected, individuals. No increase in proliferative response to CMV Ag was observed. CD40LT exerted its effect through B7-CD28-dependent and IL-12- and IL-15-independent mechanisms. Finally, the increase in proliferation with CD40LT and IL-12 was associated with an augmented production of IFN-gamma in most, but not all, individuals. These data suggest the possible contribution of HIV-specific unresponsiveness to the lack of CD4+ T cell proliferation to p24 Ag in HIV-infected individuals and that clonal deletion alone does not explain this phenomenon. They also indicate the potential for CD40LT and IL-12 as immune-based therapies for HIV infection.
Asunto(s)
Adyuvantes Inmunológicos/fisiología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/metabolismo , Anergia Clonal/inmunología , Proteína p24 del Núcleo del VIH/inmunología , Interferón gamma/biosíntesis , Interleucina-12/fisiología , Activación de Linfocitos/inmunología , Glicoproteínas de Membrana/fisiología , Fármacos Anti-VIH/uso terapéutico , Antígeno B7-1/fisiología , Antígenos CD28/fisiología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Ligando de CD40 , Células Cultivadas , Relación Dosis-Respuesta Inmunológica , Sinergismo Farmacológico , Epítopos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Interleucina-12/uso terapéutico , Interleucina-15/fisiología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Ligandos , Glicoproteínas de Membrana/uso terapéuticoRESUMEN
Bacteriophage phiX174 immunization was used to measure CD4(+) T cell function in vivo in human immunodeficiency virus (HIV)-infected patients across all disease stages. Function was evaluated by measuring the ability of T cells to provide help to B cells in antibody production, amplification, and isotype switching. A total of 33 patients and 10 controls received 3 bacteriophage phiX174 immunizations 6 weeks apart. The patients' responses regarding bacteriophage-specific total antibody titers and IgG titers were quantitatively and qualitatively inferior to the controls' responses. Overall, 7 of 33 patients had normal T cell function. Baseline CD4 counts provided the strongest correlation with total antibody and IgG titers. HIV RNA had a weaker association with responses but had some predictive power among patients with a CD4 count >200 cells/microL. Bacteriophage phiX174 immunization seems to be a useful tool for measuring immune function in vivo, which suggests that most HIV-infected patients may have abnormal CD4(+) T cell function despite adequate antiretroviral treatment.
Asunto(s)
Infecciones por VIH/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Formación de Anticuerpos , Linfocitos B/inmunología , Bacteriófago phi X 174/inmunología , Femenino , Sobrevivientes de VIH a Largo Plazo , Humanos , Cambio de Clase de Inmunoglobulina , Memoria Inmunológica , Masculino , Subgrupos de Linfocitos T , VacunaciónRESUMEN
Although efavirenz-containing regimens effectively suppress plasma levels of human immunodeficiency virus (HIV) RNA, it is now clear that undetectable plasma viremia may not reflect a lack of viral replication. Because lymphoid tissue is an active site of HIV replication, the lymph node virus burden was analyzed in persons who received highly active antiretroviral therapy (HAART) containing either efavirenz or a protease inhibitor (PI). Testing with in situ hybridization revealed no detectable follicular dendritic cell-associated HIV RNA in either group, and only 2 of 8 persons in the efavirenz group and 1 of 4 in the PI group had detectable RNA in lymph node mononuclear cells (LNMC) when tested by use of nucleic acid sequencebased amplification. Low levels of replication-competent HIV were identified in both groups by use of quantitative coculture assays. There was no evidence of development of resistance to either regimen in virus isolated from LNMC. These data support the use of efavirenz as an alternative to a PI in initial HAART regimens.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/virología , Ganglios Linfáticos/virología , Oxazinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Alquinos , Benzoxazinas , Técnicas de Cocultivo , Estudios Transversales , Ciclopropanos , Genotipo , VIH/genética , VIH/fisiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Hibridación in Situ , Ganglios Linfáticos/patología , Inhibidores de Proteasas/uso terapéutico , ARN Viral/análisis , Carga Viral , Replicación ViralRESUMEN
OBJECTIVES: To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART). METHODS: Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA. RESULTS: Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels. CONCLUSION: Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/patología , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Proteína p24 del Núcleo del VIH/sangre , Ganglios Linfáticos/patología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Depleción Linfocítica , Microscopía Electrónica , Carga ViralRESUMEN
The size of the pool of resting CD4+ T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4+ T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4+ T cells that contain replication-competent HIV.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Interleucina-2/uso terapéutico , Estudios Transversales , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/patogenicidad , Humanos , Interleucina-2/farmacología , Ganglios Linfáticos/virología , Recuento de Linfocitos/efectos de los fármacos , ARN Viral/sangre , Replicación Viral/efectos de los fármacosRESUMEN
The chemokine receptors CXCR4 and CCR5 have been identified as major coreceptors for HIV-1 entry into CD4+ T cells. The majority of primary HIV-1 isolates in early disease use CCR5 as a coreceptor, whereas during disease progression with the emergence of syncytium-inducing viruses, CXCR4 is also used. We performed a cross-sectional study in which we evaluated the expression of two HIV-1 coreceptors, CCR5 and CXCR4, in whole blood samples taken from HIV-1-infected and uninfected individuals. We demonstrate that CXCR4 on CD4+ and CD8+ T cells, and CD14+ monocytes is significantly down-regulated, and CCR5 expression on CD4+ T cells is up-regulated in HIV-infected individuals compared with uninfected controls. Coreceptor expression correlated with the level of cellular activation in vivo in both HIV-infected and uninfected individuals, with CXCR4 being expressed predominantly on quiescent (HLA-DR-) T cells and CCR5 being expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. In addition, a tendency for greater activation of CXCR4+CD4+ T cells in patients with advanced disease was observed. Patients who harbored syncytium-inducing viruses, however, could not be distinguished from those who harbored nonsyncytium-inducing viruses based on the level of CD4+ T cell activation or chemokine receptor expression.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Receptores CCR5/biosíntesis , Receptores CXCR4/biosíntesis , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Seronegatividad para VIH/inmunología , Seropositividad para VIH/inmunología , VIH-1/aislamiento & purificación , VIH-1/metabolismo , Humanos , Leucocitos/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Fenotipo , Receptores CCR5/sangre , Receptores CXCR4/sangre , Linfocitos T/inmunologíaRESUMEN
The immunodeficiency caused by human immunodeficiency virus (HIV) infection may be related to loss of diversity in the T cell receptor (TCR) repertoire. A cross-sectional study of the CD4 TCR repertoire was done for patients at various stages of HIV infection. Semiquantitative polymerase chain reaction was used to study the relative usage of the variable chain beta (BV) subfamilies and the size distributions of transcripts (CDR3 size analysis) within these subfamilies. The relative usage of the TCRBV subfamilies of patients and controls was not significantly different. The proportion of subfamilies with abnormal CDR3 size patterns was higher in the HIV-infected patients (25%, 95% confidence interval [CI], 17%-33%) than in the controls (7.2%, 95% CI, 2.3%-12.1%; P < .001), with a significant negative correlation between the number of CD4 cells and the percentage of abnormal TCRBV subfamilies. These results indicate that progressive loss of CD4 T cells is accompanied by increasing disruptions within the T cell receptor repertoire.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Complejo Receptor-CD3 del Antígeno de Linfocito T/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Recuento de Linfocito CD4 , Estudios Transversales , Humanos , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Análisis de Secuencia de ADNRESUMEN
Although highly active antiretroviral therapy (HAART) in the form of triple combinations of drugs including protease inhibitors can reduce the plasma viral load of some HIV-1-infected individuals to undetectable levels, it is unclear what the effects of these regimens are on latently infected CD4+ T cells and what role these cells play in the persistence of HIV-1 infection in individuals receiving such treatment. The present study demonstrates that highly purified CD4+ T cells from 13 of 13 patients receiving HAART with an average treatment time of 10 months and with undetectable (<500 copies HIV RNA/ml) plasma viremia by a commonly used bDNA assay carried integrated proviral DNA and were capable of producing infectious virus upon cellular activation in vitro. Phenotypic analysis of HIV-1 produced by activation of latently infected CD4+ T cells revealed the presence in some patients of syncytium-inducing virus. In addition, the presence of unintegrated HIV-1 DNA in infected resting CD4+ T cells from patients receiving HAART, even those with undetectable plasma viremia, suggests persistent active virus replication in vivo.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/virología , VIH-1/fisiología , Latencia del Virus , Linfocitos T CD4-Positivos/virología , ADN Viral , Células Gigantes , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Replicación ViralRESUMEN
BACKGROUND: Indinavir, a protease inhibitor widely used to treat patients with HIV infection, has been associated with nephrolithiasis. Distinctive urinary crystals and a spectrum of urologic disorders were noted in patients receiving indinavir. OBJECTIVE: To determine the composition of urinary crystals and the frequency of asymptomatic crystalluria and urinary tract symptoms in patients receiving indinavir. PATIENTS: Patients with HIV infection who were enrolled in studies conducted at the National Institutes of Health. MEASUREMENTS: Microscopic urinalysis, high-performance liquid chromatography (HPLC) and mass spectrometry of urinary crystals and stones, and clinical evaluation of patients with urologic symptoms. RESULTS: Of 240 patients receiving indinavir, 142 provided urine specimens for analysis. Twenty-nine (20%) had crystals consisting of plate-like rectangles and fan-shaped or starburst forms. Mass spectrometry and HPLC confirmed that these crystals were composed of indinavir. Of 40 patients who were not receiving indinavir, none had similar crystals (P < 0.001). Nineteen of the 240 patients receiving indinavir (8%) developed urologic symptoms. Of these, 7 (3%) had nephrolithiasis and the other 12 (5%) had previously undescribed syndromes: crystalluria associated with dysuria and crystalluria associated with back or flank pain. Four of the patients with the latter syndrome had radiographic evidence of intrarenal sludging. CONCLUSIONS: Indinavir forms characteristic crystals in the urine. This crystalluria may be associated with dysuria and urinary frequency, with flank or back pain associated with intrarenal sludging, and with the classic syndrome of renal colic.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Inhibidores de la Proteasa del VIH/efectos adversos , Indinavir/efectos adversos , Enfermedades Urológicas/inducido químicamente , Enfermedades Urológicas/orina , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Cálculos Renales/inducido químicamente , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Dolor/inducido químicamente , Factores de Riesgo , Trastornos Urinarios/inducido químicamente , Orina/químicaRESUMEN
PURPOSE: To study the imaging findings in patients with systemic mastocytosis and to correlate the findings with the severity of disease on the basis of an established classification system. Pathologic findings, when available, were correlated with imaging findings. MATERIALS AND METHODS: Computed tomographic (CT) and ultrasound (US) scans and corresponding pathologic findings, when available, were retrospectively reviewed in 27 patients with systemic mastocytosis. RESULTS: Only five (19%) of the patients in our series had normal abdominal CT and/or US examination results. Common abdominal imaging findings associated with systemic mastocytosis were hepatosplenomegaly, retroperitoneal adenopathy, periportal adenopathy, mesenteric adenopathy, thickening of the omentum and the mesentery, and ascites. Less common findings included hepatofugal portal venous flow, Budd-Chiari syndrome, cavernous transformation of the portal vein, ovarian mass, and complications such as chloroma. The findings were more common in patients with category II and those with category III disease. CONCLUSION: Abdominal findings at CT and US are common in patients with systemic mastocytosis. Although the findings in patients with systemic mastocytosis are not specific to the disease, they are useful in directing further studies for diagnostic confirmation and in estimating the extent of systemic involvement.
Asunto(s)
Abdomen/diagnóstico por imagen , Mastocitosis/diagnóstico por imagen , Radiografía Abdominal , Tomografía Computarizada por Rayos X , Adulto , Anciano , Femenino , Humanos , Masculino , Mastocitosis/complicaciones , Persona de Mediana Edad , Estudios Retrospectivos , UltrasonografíaRESUMEN
We report the cases of three HIV-positive patients with solitary pulmonary nodules caused by Cryptococcus neoformans. Although human infection with C. neoformans occurs via the respiratory tract, isolated pulmonary infection in HIV-positive patients, in contrast with HIV-negative patients, has been thought to be relatively rare. When isolated pulmonary disease in HIV-infected patients, has been described, most of the patients have been symptomatic (symptoms have included fever, cough, and dyspnea). In addition, these patients have had diffuse interstitial infiltrates, alveolar infiltrates, or nodular infiltrates that have often been associated with hilar adenopathy and occasionally with pleural effusions. None of the patients in the previously reported series have had lesions described as small, asymptomatic, isolated pulmonary nodules.
Asunto(s)
Criptococosis/diagnóstico , Cryptococcus neoformans , Infecciones por VIH/complicaciones , Adulto , Homosexualidad Masculina , Humanos , Pulmón/patología , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Mastocytosis is a disease of mast cell hyperplasia that may involve several organ systems, including liver. Between 1988 and 1991, we conducted a retrospective-prospective study of 41 patients with mastocytosis and found 61% had evidence of liver disease. Hepatomegaly was detected in 24%, splenomegaly in 41%, and elevated serum alkaline phosphatase, serum aminotransaminases, 5'nucleotidase, or gamma-glutamyltranspeptidase (GGTP) in 54% of the patients. Alkaline phosphatase levels directly correlated with GGTP levels, hepatomegaly, splenomegaly, and liver mast cell infiltration and fibrosis. Elevated alkaline phosphatase levels and splenomegaly were observed more frequently in patients with categories II and III mastocytosis. Five patients in combined disease categories II or III developed ascites or portal hypertension and died of complications of mastocytosis; three had hypoprothrombinemia at the time of death. Thirty-five liver biopsy specimens from 25 patients were examined. Mast cell infiltration was commonly observed in the biopsy specimens, more severe in those patients with either category II or III disease, and correlated with hepatomegaly, splenomegaly, alkaline phosphatase levels, and GGTP levels. Mast cells were often only detected by using special stains (toluidine blue and chloracetate esterase). Increased portal fibrosis was seen in 68% of the biopsy specimens and correlated with mast cell infiltration and portal inflammation. Cirrhosis was not observed. Nodular regenerative hyperplasia, portal venopathy, and venoocclusive disease was observed in eight biopsy specimens and may have been the cause of the portal hypertension or ascites in four patients. These findings demonstrate that liver disease with mast cell infiltration is a common finding in patients with mastocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)